Malaria is one of the oldest and most widespread infectious diseases plaguing mankind. Among human parasitic diseases, it is the most deadly. It is endemic in developing countries and infects over 500 million people each year, killing over 2.7 million of them. Thanks in part to new treatments for the disease, during the middle part of the 20th century the incidence of malaria was decreasing each year. In recent years, however, cases of malaria have dramatically increased worldwide including thousands of cases in the United States. This increase is due in part to the emergence of drug resistant strains of the disease.
Malaria is caused by eukaryotic protozoans of the genus Plasmodium. Of the 100 species of Plasmodium, four are known to cause malaria in humans. Three of these species, Plasmodium vivax, Plasmodium malariae, and Plasmodium ovale cause relatively benign forms of the disease. The fourth species, Plasmodium falciparum, is malignant and the most lethal, being responsible for the majority of deaths from malaria world wide.
P. falciparum malaria is introduced into human hosts through a bite from the female Anopheles mosquito. An infected mosquito will bite a human and inject a small amount of saliva with anticoagulant and haploid sporozoites of the P. falciparum parasite. The sporozoites enter the circulatory system and reach the liver in an hour or so. In the liver they will enter hepatic parenchymal cells in what is called the exoerythrocytic stage of the disease cycle. During the 5-7 days of this stage, they will undergo multiple asexual fission, schizogony, multiplying 30,000 to 40,000-fold, and produce merozoites.
As merozoites, they will leave the liver, reenter the bloodstream, invade erythrocytes (red blood cells), and begin the erythrocytic stage. Once inside the erythrocyte, P. falciparum begins to enlarge as an uninucleate trophozoite. Over another 1-3 days, this trophozoite will divide asexually to produce a schizont containing 6-24 nuclei. The schizont will divide and produce mononucleated merozoites. This causes the erythrocyte to lyse and release merozoites into the blood stream to infect other erythrocytes.
Some merozoites will differentiate into macrogametocytes and microgametocytes, which do not cause erythrocytes to lyse. These male and female sexual forms can be ingested by a mosquito, in which they will be fertilized to form zygotes which will produce sporozoites in the mosquito's salivary glands to permit reinfection of other human hosts.
Malaria is asymptomatic until the erythrocytic stage when the synchronized release of merozoites and debris from erythrocytes into the circulation causes the classical malarial signs and symptoms. These include paroxysms (spasms and convulsions), high fever, rigors (stiffness and chills), profuse sweating, vomiting, anemia, headache, muscle pains, spleen enlargement, and hypoglycemia. Since the release of merozoites occurs every 48 hours or so in P. falciparum malaria, the symptoms are tertian, occurring every third day. In between merozoite releases of the erythrocytic stage, a human host will feel normal and be asymptomatic.
The most severe consequence of P. falciparum malaria is the aggregation, clumping, or sludging of infected erythrocytes, including adherence to blood vessel walls. Depending on the site of the sludging, life threatening effects can occur due to the restriction of blood flow to vital organs. These include encephalopathy for cerebral malaria, pulmonary edema, acute renal failure, severe intravascular hemolysis, and hemoglobinuria. The vast majority of deaths caused by P. falciparum malaria are due to these effects.
Traditional treatments of malaria are based on either the control of mosquito populations, vaccines, or chemotherapy. For chemotherapy, drugs are generally targeted at specific stages of the disease. Such drugs include tissue schizonticides, such as chloroquine, used to eradicate the exoerythrocytic stage in the liver; blood schizonticides, such as chloroquine, folate antagonists, and the 8-aminoquinolines referred to as pyrimethamine, primaquine, and pamaquine, used to destroy the erythrocytic stage; gametocytocides, such as 4-aminoquinolines, used to kill gametocytes; and sporonticides used to kill sporozoites.
In recent years, the most effective treatment for malaria, particularly for P. falciparum malaria, has been the 4-aminoquinoline, chloroquine. This drug of choice to treat the disease is active against the erythrocytic form of P. vivax and P. falciparum. Chloroquine acts as a blood schizonticidal agent and rarely produces serious side effects. It inhibits nucleic acid and protein synthesis in protozoal cells. It is used both for the treatment of acute onset malignant tertian P. falciparum malaria and prophylactically.
It has been the prophylactic use of many chemotherapeutic treatments for malaria that has led to the emergence of drug resistant strains of Plasmodium species that cause malaria. Plasmodium resistance to chloroquine has now become widespread and is a serious problem. This has lead to the development of alternative chemotherapeutic agents.
Compounds to emerge include folate antagonists, including sulfones and sulfonamides, such as dapsone, sulfadoxine, sulfadiazine, and sulfalene; primines, and biguanides. These compounds compete with p-aminobenzoic acid (PABA), interfere with synthesis of tetrahydrofolic acid, and act as blood schizonticides. However, their effective doses can be extremely toxic and Plasmodium can readily develop resistance to these drugs.
The ability of Plasmodium species to develop resistance to drugs coupled with the undesirable side effects of such drugs has resulted in the constant development of new treatments. Thus, there are numerous compounds currently available, or in development, for the treatment of malaria.
Antiprotozoal compounds that can be or have been used as treatments against malaria may be found by referring to Goodman and Gilman's The Pharmacological Basis of Therapeutics, Eighth Edition, McGraw-Hill, Inc. (1993), Chapter 41, pages 978-998.
As indicated above, strains of P. falciparum that are resistant to one or more of the available treatments for malaria are ubiquitous today. As new compounds to attack the parasite directly are developed, a new resistant strain emerges. Additionally, the continued undesirable side effects of available drugs present problems. This is particularly true when multiple drugs must be administered to battle concurrent infections of more than one Plasmodium species, which have become quite common. Thus, not only are yet more alternative chemotherapeutic treatments for malaria desired, particularly for P. falciparum malaria, but also entirely new mechanisms of action for the eradication of the Plasmodium parasite are desired. Such mechanisms may make it more difficult for strains of the parasite to emerge that are resistant to these new drugs.